Establishment of RNA Modification Regulators Index Predicting Clinical Outcomes and Immune Relevance of Kidney Cancer Patients

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 Dec 6

PMID 39640638

Authors

Gang Li

Jingmin Cui

Shuang He

Xiufang Feng

Wenhan Li

Tao Li

Peilin Chen

Affiliations

Soon will be listed here.

Abstract

Increasing evidence indicates that RNA modifications are misregulated in human cancers, which might be optimal targets of cancer therapy. However, important RNA regulators in kidney cancer still need further exploration. In this study, we collected regulators representing different types of RNA modification and identified the prognosis-related RNA regulators in kidney cancer patients. We further constructed a 4-gene RNA regulators signature and index called prognosis-related RNA regulators index (PRRI) by the Lasso-Cox regression algorithm. We found that PRRI could precisely predict prognosis of patients in the KIRC training (AUC at 3-/5-/7-years = 0.7132/0.7220/0.7283) and testing cohorts (AUC at 3-/5-/7-years = 0.7141/0.7403/0.7305) and two independent RCC cohorts - E-MTAB-1980 (AUC at 3-/5-/7-years = 0.7036/0.7385/0.7143) and KIRP (AUC at 3-/5-/7-years = 0.6203/0.6365/0.6941). Moreover, the high PRRI group showed a worse clinical outcome than the low PRRI group. PRRI demonstrated strong robustness and was related to histological grade and pathologic stage, which was also found to be an independent prognosis factor when other clinical variables adjusted it. We further found several immune-related pathways differentially enriched in the high or low PRRI group. The regulation of T cell migration, which has been proven to be an immunosuppressive cell, shows a high enrichment in the high PRRI group. Further analysis reveals that PRRI also shows a highly positive correlation with the activity of Tregs. TIDE analysis and two independent immune therapy cohorts revealed that the high PRRI group might resist immune therapy, while the low PRRI group might benefit from the treatment, indicating that PRRI could be a marker for predicting immune therapeutic response. All in all, we determined 4 potentially essential RNA regulators and illustrated their mechanisms concretely. Furthermore, we constructed a 4-gene index called PRRI to predict patients' outcomes and immunotherapy response.

References

Du E, Li J, Sheng F, Li S, Zhu J, Xu Y . A pan-cancer analysis reveals genetic alterations, molecular mechanisms, and clinical relevance of m C regulators. Clin Transl Med. 2020; 10(5):e180. PMC: 7507430. DOI: 10.1002/ctm2.180. View

Shi J, Liu T, Liu C, Zhang H, Ruan G, Xie H . Remnant cholesterol is an effective biomarker for predicting survival in patients with breast cancer. Nutr J. 2024; 23(1):45. PMC: 11034071. DOI: 10.1186/s12937-024-00951-3. View

Li W, Ye K, Li X, Liu X, Peng M, Chen F . YTHDC1 is downregulated by the YY1/HDAC2 complex and controls the sensitivity of ccRCC to sunitinib by targeting the ANXA1-MAPK pathway. J Exp Clin Cancer Res. 2022; 41(1):250. PMC: 9382764. DOI: 10.1186/s13046-022-02460-9. View

Pan X, Huang B, Ma Q, Ren J, Liu Y, Wang C . Circular RNA circ-TNPO3 inhibits clear cell renal cell carcinoma metastasis by binding to IGF2BP2 and destabilizing SERPINH1 mRNA. Clin Transl Med. 2022; 12(7):e994. PMC: 9309750. DOI: 10.1002/ctm2.994. View

Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, Shibata K . Prognostic value of tumor-infiltrating FOXP3+ regulatory T cells in patients with hepatocellular carcinoma. Eur J Surg Oncol. 2007; 34(2):173-9. DOI: 10.1016/j.ejso.2007.08.008. View

Zhang C, Chen L, Lou W, Su J, Huang J, Liu A . Aberrant activation of m6A demethylase FTO renders HIF2α clear cell renal cell carcinoma sensitive to BRD9 inhibitors. Sci Transl Med. 2021; 13(613):eabf6045. DOI: 10.1126/scitranslmed.abf6045. View

Han J, Wang J, Yang X, Yu H, Zhou R, Lu H . METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol Cancer. 2019; 18(1):110. PMC: 6588935. DOI: 10.1186/s12943-019-1036-9. View

McGrath P, Holley D, Hamby L, Powell D, Mattingly C, Freeman J . Proliferation-associated nucleolar antigen P120: a prognostic marker in node-negative breast cancer. Surgery. 1994; 116(4):616-20; discussion 20-1. View

Young M, Jackson-Spence F, Beltran L, Day E, Suarez C, Bex A . Renal cell carcinoma. Lancet. 2024; 404(10451):476-491. DOI: 10.1016/S0140-6736(24)00917-6. View

10.

Chen X, Li A, Sun B, Yang Y, Han Y, Yuan X . 5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs. Nat Cell Biol. 2019; 21(8):978-990. DOI: 10.1038/s41556-019-0361-y. View

11.

Liao H, Gaur A, McConie H, Shekar A, Wang K, Chang J . Human NOP2/NSUN1 regulates ribosome biogenesis through non-catalytic complex formation with box C/D snoRNPs. Nucleic Acids Res. 2022; 50(18):10695-10716. PMC: 9561284. DOI: 10.1093/nar/gkac817. View

12.

Gonzalez-Navajas J, Fan D, Yang S, Yang F, Lozano-Ruiz B, Shen L . The Impact of Tregs on the Anticancer Immunity and the Efficacy of Immune Checkpoint Inhibitor Therapies. Front Immunol. 2021; 12:625783. PMC: 7952426. DOI: 10.3389/fimmu.2021.625783. View

13.

Boccaletto P, Stefaniak F, Ray A, Cappannini A, Mukherjee S, Purta E . MODOMICS: a database of RNA modification pathways. 2021 update. Nucleic Acids Res. 2021; 50(D1):D231-D235. PMC: 8728126. DOI: 10.1093/nar/gkab1083. View

14.

Li S, Jia Z, Yang J, Ning X . Telomere-related gene risk model for prognosis and drug treatment efficiency prediction in kidney cancer. Front Immunol. 2022; 13:975057. PMC: 9523360. DOI: 10.3389/fimmu.2022.975057. View

15.

Wang Y, Ge H, Hu M, Pan C, Ye M, Yadav D . Histological tumor micronecrosis in resected specimens after R0 hepatectomy for hepatocellular carcinomas is a factor in determining adjuvant TACE: A retrospective propensity score-matched study. Int J Surg. 2022; 105:106852. DOI: 10.1016/j.ijsu.2022.106852. View

16.

Chen K, Song B, Tang Y, Wei Z, Xu Q, Su J . RMDisease: a database of genetic variants that affect RNA modifications, with implications for epitranscriptome pathogenesis. Nucleic Acids Res. 2020; 49(D1):D1396-D1404. PMC: 7778951. DOI: 10.1093/nar/gkaa790. View

17.

Li L, Zhu C, Xu S, Xu Q, Xu D, Gan S . PUS1 is a novel biomarker for evaluating malignancy of human renal cell carcinoma. Aging (Albany NY). 2023; 15(11):5215-5227. PMC: 10292901. DOI: 10.18632/aging.204799. View

18.

Li J, Kong Z, Qi Y, Wang W, Su Q, Huang W . Single-cell and bulk RNA-sequence identiﬁed ﬁbroblasts signature and CD8 + T-cell - ﬁbroblast subtype predicting prognosis and immune therapeutic response of bladder cancer, based on machine learning: bioinformatics multi-omics study. Int J Surg. 2024; 110(8):4911-4931. PMC: 11325897. DOI: 10.1097/JS9.0000000000001516. View

19.

Wang J, Zhu W, Han J, Yang X, Zhou R, Lu H . The role of the HIF-1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer. Cancer Commun (Lond). 2021; 41(7):560-575. PMC: 8286140. DOI: 10.1002/cac2.12158. View

20.

Tanaka A, Sakaguchi S . Regulatory T cells in cancer immunotherapy. Cell Res. 2016; 27(1):109-118. PMC: 5223231. DOI: 10.1038/cr.2016.151. View